Genetic variation in EPHA contributes to sensitivity to paclitaxel‐induced peripheral neuropathy

Abstract

Aims: Chemotherapy-induced peripheral neuropathy (PN) is a treatment limiting toxicity of paclitaxel. We evaluated if EPHA genetic variation (EPHA4, EPHA5, EPHA6, and EPHA8) is associated with PN sensitivity by accounting for variability in systemic paclitaxel exposure (time above threshold). Methods:Germline DNA from 60 patients with breast cancer was sequenced. PN was measured using the 8-item sensory subscale (CIPN8) of the patient-reported CIPN20. Associations for 3 genetic models were tested by incorporating genetics into previously published PN prediction models integrating measured paclitaxel exposure and cumulative treatment. Significant associations were then tested for association with PN-related treatment disruption.Results: EPHA5 rs7349683 (minor allele frequency = 0.32) was associated with increased PN sensitivity (β-coefficient = 0.39, 95% confidence interval 0.11-0.67, p = 0.007). Setting a maximum tolerable threshold of CIPN8 = 30, optimal paclitaxel exposure target is shorter for rs7349683 homozygous (11.6 h) than heterozygous (12.6 h) or wild-type (13.6 h) patients. Total number of missense variants (median = 0, range 0-2) was associated with decreased PN sensitivity (β-coefficient: −0.42, 95% confidence interval −0.72 to −0.12, P = .006). No association with treatment disruption was detected for the total number of missense variants or rs7349683. Conclusion:Isolating toxicity sensitivity by accounting for exposure is a novel approach, and rs7349683 represents a promising marker for PN sensitivity that may be used to individualize paclitaxel treatment. K E Y W O R D Sbreast cancer, genetic polymorphism, pharmacodynamics, pharmacogenomics, pharmacokinetics Principal statement: The authors confirm that the PI for this paper is D.L. Hertz and that the coinvestigator N. Lynn Henry had direct clinical responsibility for patients.

Pharmacogenetics of taxane‐induced neurotoxicity in breast cancer: Systematic review and meta‐analysis

“…Fifteen of them were nested designs coming from randomized controlled trials (5 case controls 7 , 23 , 24 , 25 , 26 and 10 cohorts 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ), 17 were cohort studies, 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 and 10 were case‐control studies. 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 The studies were conducted in the United States (15 studies 24 , 26 , 27 , 31 , 34 , 35 , 36 , 42 , 48 , ...…”

Mechanistic insights into the pathogenesis of microtubule‐targeting agent‐induced peripheral neuropathy from pharmacogenetic and functional studies

“…EPHA5 encodes the receptor tyrosine kinase ephrin receptor A5 which guides axonal growth during development 73 . Association of EPHA5 genetic variants with increased risk of paclitaxel‐induced peripheral neuropathy has been replicated in other studies and may be related to the inability to repair injured axons following paclitaxel treatment 69,74 . Although the GWAS that replicated the EPHA5 findings was limited by sample size and included patients treated with both paclitaxel and carboplatin (Table 3), other EPHA genes were also independently associated to CIPN and indicate that ephrin‐A signalling may be a critical function in the response to neuronal injury.…”

Analysis Approaches to Identify Pharmacogenetic Associations With Pharmacodynamics

“…Then genes involved in hereditary neuropathy that had previously been reported to increase risk of paclitaxel‐induced neuropathy were investigated, including variants in EPHA5 . Introducing those variants into the neuropathy‐prediction model demonstrated that these genotypes affect a patient’s neuropathy sensitivity after accounting for variability in cumulative paclitaxel exposure 19 . Importantly, a post hoc analysis confirmed that this association for EPHA5 would not have been detected without including measured paclitaxel PKs in the multivariable model.…”

“…Introducing those variants into the neuropathy-prediction model demonstrated that these genotypes affect a patient's neuropathy sensitivity after accounting for variability in cumulative paclitaxel exposure. 19 Importantly, a post hoc analysis confirmed that this association for EPHA5 would not have been detected without including measured paclitaxel PKs in the multivariable model. In the case of OPRM1, this approach would be attempted by first modeling the morphine-analgesia association and adding OPRM1 genotype as a covariate in the model to see if it explains residual variability in the resulting analgesic effect.…”